A broad ranging attack will be made on the chemistry and biochemistry of polyketide metabolites in a continuation of a program that has made major contributions to the field, particularly in the area of biomimetic synthesis. Work proposed for the present project period is divided into three areas of concentration. The first area is the development of new synthons for assembly of polycarbonyl compounds with emphasis on methods to introduce C-methyl groups along the chain and functionality at the terminus. The second area involves syntheses of specific polycarbonyl compounds and their use in biomimetic syntheses of polyketide metabolities or compounds suspected of being metabolites. Important goals in this area include the pretetramide and protetrone precursors of the tetracycline antibiotics. The third area of study involves the use of the various synthetic compounds in metabolic experiments. Protetrones and pretetramides will be used to shed light on the timing of introduction of the methyl group at position 6 and removal of the hydroxyl group at position 8 of tetracycline. Attempts will be made to form novel tetracyclines from unnatrual pretetramides. Synthetic enol lactones of polyketo acids will be used to isolate these lactones by carrier dilution techniques from suitable fungal systems. It is speculated that the lactones are shunt products of metabolic pathways leading to aromatic compounds. Fungal systems elaborating griseofluvin, stipitatic acid and sepedonin will be investigated.